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Cited by 134Colorectal Cancer Treatments and StudiesCancer Immunotherapy and BiomarkersGenetic factors in colorectal cancer

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Temozolomide Followed by Combination With Low-Dose Ipilimumab and Nivolumab in Patients With Microsatellite-Stable, O6-Methylguanine–DNA Methyltransferase–Silenced Metastatic Colorectal Cancer: The MAYA Trial

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Morano, Federica, Raimondi, Alessandra, Pagani, Filippo, Lonardi, Sara, Salvatore, Lisa, Cremolini, Chiara, Murgioni, Sabina, Randon, Giovanni, Palermo, Federica, Antonuzzo, Lorenzo, Pella, Nicoletta, Racca, Patrizia, Prisciandaro, Michele, Niger, Monica, Corti, Francesca, Bergamo, Francesca, Zaniboni, Alberto, Ratti, Margherita, Palazzo, Michele, Cagnazzo, Celeste, Calegari, Maria Alessandra, Marmorino, Federica, Capone, Iolanda, Conca, Elena, Busico, Adele, Brich, Silvia, Tamborini, Elena, Perrone, Federica, Di Maio, Massimo, Milione, Massimo, Di Bartolomeo, Maria, de Braud, Filippo, Pietrantonio, Filippo·2022·Journal of Clinical Oncology
DOI 10.1200/jco.21.02583PMC PMC9084437
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Abstract

PURPOSE: This is a multicenter, single-arm phase II trial evaluating the efficacy and safety of an immune-sensitizing strategy with temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab in patients with microsatellite-stable (MSS) and O 6-methylguanine–DNA methyltransferase (MGMT)–silenced metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with pretreated mCRC were centrally prescreened for MSS status and MGMT silencing (ie, lack of MGMT expression by immunohistochemistry plus MGMT methylation by pyrosequencing). Eligible patients received two priming cycles of oral temozolomide 150 mg/sqm once daily, days 1-5, once every 4 weeks (first treatment part) followed, in absence of progression, by its combination with ipilimumab 1 mg/kg once every 8 weeks and nivolumab 480 mg once every 4 weeks (second treatment part). The primary end point was the 8-month progression-free survival (PFS) rate calculated from enrollment in patients who started the second treatment part, with ≥ 4 out of 27 subjects progression-free by the 8-month time point as decision rule. RESULTS: Among 716 prescreened patients, 204 (29%) were molecularly eligible and 135 started the first treatment part. Among these, 102 (76%) were discontinued because of death or disease progression on temozolomide priming, whereas 33 patients (24%) who achieved disease control started the second treatment part and represented the final study population. After a median follow-up of 23.1 months (interquartile range, 14.9-24.6 months), 8-month PFS rate was 36%. Median PFS and overall survival were 7.0 and 18.4 months, respectively, and overall response rate was 45%. Grade 3-4 immune-related adverse events were skin rash (6%), colitis (3%), and hypophysitis (3%). No unexpected adverse events or treatment-related deaths were reported. CONCLUSION: The MAYA study provided proof-of-concept that a sequence of temozolomide priming followed by a combination of low-dose ipilimumab and nivolumab may induce durable clinical benefit in MSS and MGMT-silenced mCRC.

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Crossref · 10.1200/jco.21.02583

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FIG 1. Trial Design. This figure depicts the design of the MAYA study, divided into the first treatment part with two cycles of temozolomide priming and the second treatment part, including combination of temozolomide and nivolumab plus low-dose ipilimumab. aRebiopsy (optional). CT, computed tomography; CR, complete response; IPI, ipilimumab; NIVO, nivolumab; PD, progressive disease; PR, partial response; SD, stable disease; TMZ, temozolomide.
FIG 1. Trial Design. This figure depicts the design of the MAYA study, divided into the first treatment part with two cycles of temozolomide priming and the second treatment part, including combination of temozolomide and nivolumab plus low-dose ipilimumab. aRebiopsy (optional). CT, computed tomography; CR, complete response; IPI, ipilimumab; NIVO, nivolumab; PD, progressive disease; PR, partial response; SD, stable disease; TMZ, temozolomide.CC BY-NC-ND · PubMed Central
FIG 2. Flow diagram of the trial. aFrom March 2019 to November 2020 across 12 Italian sites. TMZ, temozolomide.
FIG 2. Flow diagram of the trial. aFrom March 2019 to November 2020 across 12 Italian sites. TMZ, temozolomide.CC BY-NC-ND · PubMed Central
FIG 3. Kaplan-Meier curves for (A) PFS and (B) OS of patients in the second treatment part. OS, overall survival; PFS, progression-free survival.
FIG 3. Kaplan-Meier curves for (A) PFS and (B) OS of patients in the second treatment part. OS, overall survival; PFS, progression-free survival.CC BY-NC-ND · PubMed Central
FIG 4. (A) Waterfall plot with the best tumor response achieved by each patient; (B) spider plot with dynamics of tumor response; (C) swimmer plot with treatment duration for each patient in the second treatment part, with the time points of occurrence of PR, first PD, and second PD. At the time of the data cutoff (December 17, 2021), 11 patients were still on study in the second treatment part: treatment was still ongoing in 10 patients (black arrows) without disease progression in six and beyond progression in four. One patient discontinued the treatment because of immune-related toxicity. Main reasons for study discontinuation in the 22 remaining patients were disease progression (n = 19) and death (n = 3, because of clinical progression in one and COVID-19 during the first outbreak in Italy in two). PFS, progression-free survival; PR, partial response; SD, stable disease.
FIG 4. (A) Waterfall plot with the best tumor response achieved by each patient; (B) spider plot with dynamics of tumor response; (C) swimmer plot with treatment duration for each patient in the second treatment part, with the time points of occurrence of PR, first PD, and second PD. At the time of the data cutoff (December 17, 2021), 11 patients were still on study in the second treatment part: treatment was still ongoing in 10 patients (black arrows) without disease progression in six and beyond progression in four. One patient discontinued the treatment because of immune-related toxicity. Main reasons for study discontinuation in the 22 remaining patients were disease progression (n = 19) and death (n = 3, because of clinical progression in one and COVID-19 during the first outbreak in Italy in two). PFS, progression-free survival; PR, partial response; SD, stable disease.CC BY-NC-ND · PubMed Central

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  1. Jacques FH, 2021, Neurooncol Adv, 3, vdab118

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Metadata

Authors
Morano, F., Raimondi, A., Pagani, F., Lonardi, S., Salvatore, L., Cremolini, C., Murgioni, S., Randon, G., Palermo, F., Antonuzzo, L., Pella, N., Racca, P., Prisciandaro, M., Niger, M., Corti, F., Bergamo, F., Zaniboni, A., Ratti, M., Palazzo, M., Cagnazzo, C., Calegari, M. A., Marmorino, F., Capone, I., Conca, E., Busico, A., Brich, S., Tamborini, E., Perrone, F., Di Maio, M., Milione, M., Di Bartolomeo, M., de Braud, F., & Pietrantonio, F.
Affiliations
  • Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
  • Istituto Oncologico Veneto (IT)
  • Università Cattolica del Sacro Cuore (IT)
  • University of Pisa (IT)
  • Azienda Ospedaliero-Universitaria Careggi (IT)
  • University of Udine (IT)
  • Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT)
  • Fondazione Poliambulanza Istituto Ospedaliero (IT)
  • Azienda Socio Sanitaria Territoriale di Cremona (IT)
  • University of Turin (IT)
  • Agostino Gemelli University Polyclinic (IT)
  • Department of Oncology, University of Turin, Division of Medical Oncology, Ordine Mauriziano Hospital, Turin, Italy
  • Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Corresponding author
Pietrantonio, Filippo
ORCID
Venue
Journal of Clinical Oncology
Publisher
American Society of Clinical Oncology (ASCO)
Published
2022-05-10
Volume
40
Issue
14
Pages
1562-1573
ISSN
  • 0732-183X (ISSN-L)
  • 1527-7755
DOI
10.1200/jco.21.02583
PMC
PMC9084437
OpenAlex
W4220750583
Cited by
134
References
37
Citations by year
2026: 18 · 2025: 33 · 2024: 32 · 2023: 36 · 2022: 15
FWCI
12.14
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Journal of Clinical Oncology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Florence Research (University of Florence) (submittedVersion, cc-by-nc-nd)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, cc-by-nc-nd)
  • ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
  • PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords
temozolomide, ipilimumab, nivolumab, metastatic colorectal cancer, microsatellite stable, immune checkpoint inhibitors, progression-free survival, immune-related adverse events, MGMT promoter methylation, combination immunotherapy
MeSH terms
Ipilimumab, Temozolomide, Nivolumab, Antineoplastic Combined Chemotherapy Protocols, Colonic Neoplasms, Humans, Rectal Neoplasms, Colorectal Neoplasms, Microsatellite Repeats, O(6)-Methylguanine-DNA Methyltransferase

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